Conceptus membranes, or trophectoderm, of various mammals produce biochemical signals that allow for the establishment and maintenance of pregnancy (Bazer, et al., 1983). One such protein, ovine trophoblast protein-one (oTP-1), was identified as a low molecular weight protein secreted by sheep conceptuses between days 10 and 21 of pregnancy (Wilson, et al., 1979; Bazer, et al., 1986). The protein oTP-1 was shown to inhibit uterine secretion of prostaglandin F.sub.2 -alpha, which causes the corpus luteum on the ovary to undergo physiological and endocrinological demise in nonpregnant sheep (Bazer, et al., 1986). Accordingly, oTP-1 has antiluteolytic biological activity. The primary role of oTP-1 was assumed to be associated with the establishment of pregnancy.
oTP-1 was subsequently found to (i) exhibit limited homology (50-70%) with interferon alphas (IFN.alpha.) of various species (Imakawa, et al., 1987), and (ii) bind to a Type I interferon receptor (Stewart, et al., 1987). Despite some similarities with IFN.alpha., oTP-1 has several features that distinguish it from IFN.alpha. including the following: oTP-1's role in reproductive biochemistry (other interferons are not known to have any role in the biochemical regulation of reproductive cycles), oTP-1's cellular source--trophoblast cells (IFN.alpha. is derived from lymphocyte cells), oTP-1's size--172 amino acids (IFN.alpha. is typically about 166 amino acids), and oTP-1 is weakly inducible by viruses (IFN.alpha. is highly inducible by viruses). The International Interferon Society recognizes oTP-1 as belonging to an entirely new class of interferons which have been named interferon-tau (IFN.tau.). The Greek letter.tau. stands for trophoblast.
The interferons have been classified into two distinct groups: type I interferons, including IFN.alpha., IFN.beta., and IFN.omega. (also known as IFN.alpha.II); and type II interferons, represented by IFN.gamma. (reviewed by DeMaeyer, et al.). In humans, it is estimated that there are at least 17 IFN.alpha. non-allelic genes, at least about 2 or 3 IFN.beta. non-allelic genes, and a single IFN.gamma. gene.
IFN.alpha.'s have been shown to inhibit various types of cellular proliferation. IFN.alpha.'s are especially useful against hematologic malignancies such as hairy-cell leukemia (Quesada, et al., 1984). Further, these proteins have also shown activity against multiple myeloma, chronic lymphocytic leukemia, low-grade lymphoma, Kaposi's sarcoma, chronic myelogenous leukemia, renal-cell carcinoma, urinary bladder tumors and ovarian cancers (Bonnem, et al., 1984; Oldham, 1985). The role of interferons and interferon receptors in the pathogenesis of certain autoimmune and inflammatory diseases has also been investigated (Benoit, et al., 1993).
IFN.alpha.'s are also useful against various types of viral infections (Finter, et al., 1991). Alpha interferons have shown activity against human papillomavirus infection, Hepatitis B, and Hepatitis C infections (Finter, et al., 1991; Kashima, et al., 1988; Dusheiko, et al., 1986; Davis, et al., 1989).
Significantly, however, the usefulness of IFN.alpha.'s has been limited by their toxicity: use of interferons in the treatment of cancer and viral disease has resulted in serious side effects, such as fever, chills, anorexia, weight loss, and fatigue (Pontzer, et al., 1991; Oldham, 1985). These side effects often require (i) the interferon dosage to be reduced to levels that limit the effectiveness of treatment, or (ii) the removal of the patient from treatment. Such toxicity has reduced the usefulness of these potent antiviral and antiproliferative proteins in the treatment of debilitating human and animal diseases.